Natural killer (NK) cells play a critical role in immunity to some viruses and they protect against hematopoietic malignancy but their uncontrolled activity can lead to pathology due to excess cytokine production and inflammation. One goal of our research is to identify the transcriptional networks that control the development and function of NK cells. Previous studies from our laboratory showed that the ETS1 transcription factor is an important regulator of NK cell development and function and limits activation of NK cells in response to endogenous cytokine. In this grant, mice with a conditional allele of Ets1 will be used to delete Ets1 from mature NK cells providing a model system that will allow us to test the hypothesis that ETS1 has distinct but essential requirements during development, maturation, and activation of NK cells. An understanding of the molecular mechanisms controlling development and activation of NK cells will provide a foundation on which to control their function in situations of immune deficiency or hyper-activity when control of NK cell function would be beneficial, such as for immunotherapy.